Customising lactacystins: studies towards the total synthesis of lactacystin and its analogues

Horton, Alexandra (2015) Customising lactacystins: studies towards the total synthesis of lactacystin and its analogues. Doctoral thesis, University of East Anglia.

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Abstract

This thesis consists of four chapters. The first contains a literature review of the isolation, previous total syntheses, biological activity and structure activity relationships of lactacystin and its analogues. Chapter two discusses our work towards the total synthesis of lactacystin and its analogues starting from three different amino acids. Chapter three contains the experimental details of our work, and the final chapter contains the details of our work on the biological testing of some of our advanced intermediates towards deoxylactacystin.
Our synthetic approach towards lactacystin and its analogues starts from a simple amino acid derivative; using different amino acid derivatives as starting material, the C5 position is easily altered. The starting material is then advanced to a suitable diester for
Dieckmann cyclization to form the lactam core found in the natural product.
The next key step in our approach follows Mander’s acylation protocol to form the C5 quaternary centre using methyl cyanoformate to install a methyl ester group in a selective manner. This step results in the fully functionalized core of lactacystin.
At this stage we had two possible routes. First, we investigated the reduction of the ketone at C6 followed by attempted decarboxylation at C7; this route ultimately proved unsuccessful. The second route inverted the reaction order; performing the decarboxylation at C7 first followed by attempts to reduce the ketone at C6. The reduction was unsuccessful and so a thiomethyl derivative was employed to allow the ketone to be successfully reduced followed by removal of the thiomethyl group using Raney nickel.
Chapter four has been written as a stand-alone chapter. Four advanced intermediates towards deoxylactacystin were chosen to undergo biological testing. Compounds were tested for their anti-proliferative effects against the HL-60 cell line using an MTS assay and their ability to inhibit the chymotrypsin-like activity in the 20S proteasome.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry
Depositing User:	Jackie Webb
Date Deposited:	18 Feb 2016 14:47
Last Modified:	18 Feb 2016 14:47
URI:	https://ueaeprints.uea.ac.uk/id/eprint/57182
DOI:

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